Molecular characteristics and clinical outcomes of breast cancer with <i>HRAS</i> mutations.
Authors: Samuel Kareff, Estelamari Rodriguez, Richa Dawar, Asaad Trabolsi, Jesus Antonio Ocejo Gallegos, Jun Yin, Phillip Walker, Irene Kang, Matias A. Bustos, Josh Neman, Dave S. Hoon, Stephanie L. Graff, David Spetzler, Gilberto Lopes
Journal: Journal of Clinical Oncology (2022)

561 Background: The RAS pathway regulates tumorigenesis and cell proliferation. HRAS is a RAS family member that activates via farnesylation. Indirectly targeting mutant HRAS with tipifarnib, a farnesyltransferase inhibitor (FTI), recently demonstrated efficacy in head and neck tumors. We aimed to investigate the molecular characteristics and clinical outcomes of HRAS mutations (HRASmut) for any potential role as a prognostic and therapeutic biomarker in breast cancer (BC). Methods: A total of 14,013 BC tissue samples had molecular profiling, including next generation DNA (592 Gene Panel, NextSeq, or WES, NovaSeq) or RNA sequencing (NovaSeq, WTS), and immunohistochemistry analyses, at Caris Life Sciences. MAP kinase (MAPK) activation and likelihood of a tumor’s response to anti-PD1 therapy were evaluated via MAPK Pathway Activity Score (MAPS) and interferon (IFN) score, respectively. Wilcoxon, Fisher’s exact, or Dunnett’s tests were used to determine statistical significance. Overall survival (OS) was calculated from date of tissue collection to insurance claims last contact using the Kaplan-Meier method. HRAS mutations (HRASmut) were compared to the general BC cohort (GC). Results: HRASmut were significantly enriched in older patients (median 69 vs 60 yrs; q&lt;.0001), and in primary compared to metastatic BC tumor samples (55.9% vs 41.9%, p&lt;.05). There were 70 total HRASmut (0.5%): Q61 was the most frequent (41.4%), followed by G12 (28.6%) and G13 (24.3%). Patients with Q61 HRASmut had significantly worse OS compared to GC (HR 1.86, 95% CI [1.10-3.13]; p&lt;0.05). HRASmut had significantly higher MPAS compared to GC (1.26, all; 1.31, Q61; 1.7, G12; -.39, GC, q&lt;.01). HRASmut were found in HR+/HER2- (22.6%) and TNBC (77.4%) tumors, but no HR-/HER2+ BC. TNBC samples with HRASmut displayed more PIK3CA (62.5% VS. 18.9%, q&lt;.05) but less TP53 mutations (50% vs 84.9%, q&lt;.05), higher expression of PD-L1 (41.2% vs 10.8%, p&lt;.05) and androgen receptor (AR, 45.8% vs 24.4%, p&lt;.05), and more frequent ARv7 fusions (20.7% vs 4.3%, p&lt;.05) compared to HR+/HER2- (Table 1). Q61 HRASmut had the highest MPAS (2.39 vs -0.28, p&lt;.01) in TNBC, whereas G12 HRASmut displayed the highest MPAS (2.01 VS -0.47, p&lt;.05) in HR+/HER2- BC. Conversely, Q61 had the lowest IFN score (-0.45 vs -0.3) in HR+/HER2- but the highest (-0.18 vs -0.3) in TNBC. Conclusions: HRASmut were mutually exclusive with HER2+ BC. The association of Q61 HRASmut with worse survival highlights the oncogenic role of these mutations and supports therapeutic investigation using FTI. PIK3CA was significantly co-mutated in HRASmut, highlighting a potential benefit of combining PIK3CA inhibitors with tipifarnib. Overall, HRASmut displayed a subtype-specific distinct genomic landscape and may represent a key therapeutic target in BC. [Table: see text]